The overall objective of this research program is to identify and study neural processes which mediate the positively reinforcing effects of drugs with dependence liability. Using brain stimulation reward, drug self-administration, and preference tests, an effort will be made to determine the brain sites at which drugs act to produce their rewarding effects, and to elucidate the role of distinct neurotransmitter systems in modulating the rewarding property of drugs of abuse. 1) The effects of meth- and d-amphetamine, cocaine, nicotine, ethanol, barbiturates, benzodiazepines, and the opiates on operant responding for rewarding stimulation of different brain sites will be examined. 2) Our recent demonstration that narcotic antagonists stereospecifically reverse the facilitatory effects of non-opiate drugs of abuse on self-stimulation responding will be further explored to elucidate the possible role of endorphins in general abuse phenomena. 3) Specific brain regions and processes mediating the reinforcing effects of drugs and their effect on brain stimulation reward will be studied by the intracerebral administration of bioactive peptides, such as enkephalin analogs and substance P, and narcotic antagonists. 4) The effects of low doses of abused drugs on serotonin and catecholamine levels and turnover in discrete brain regions will be examined using highly sensitive radioenzymatic microassays. 5) The role of specific neurotransmitter systems in mediating self-administration behavior and the effects of drugs of abuse on brain stimulation reward will be investigated by destroying distinct dopamine, norepinephrine and serotonin fiber systems and target areas by microinjection of kainic acid, 6-hydroxydopamine and 5,7-dihydroxytryptamine. These studies hopefully will lead to an increased understanding of the basic neural mechanisms by which drugs of abuse produce their euphorigenic or rewarding psychological effect, and prove valuable for the development of new approaches to the treatment of drug dependence.